@article {26, title = {Morphine hyperalgesia gated through microglia-mediated disruption of neuronal Cl$^{-}$ homeostasis.}, journal = {Nat Neurosci}, volume = {16}, year = {2013}, month = {2013 Feb}, pages = {183-92}, abstract = {

A major unresolved issue in treating pain is the paradoxical hyperalgesia produced by the gold-standard analgesic morphine and other opiates. We found that hyperalgesia-inducing treatment with morphine resulted in downregulation of the K(+)-Cl(-) co-transporter KCC2, impairing Cl(-) homeostasis in rat spinal lamina l neurons. Restoring the anion equilibrium potential reversed the morphine-induced hyperalgesia without affecting tolerance. The hyperalgesia was also reversed by ablating spinal microglia. Morphine hyperalgesia, but not tolerance, required μ opioid receptor-dependent expression of P2X4 receptors (P2X4Rs) in microglia and μ-independent gating of the release of brain-derived neurotrophic factor (BDNF) by P2X4Rs. Blocking BDNF-TrkB signaling preserved Cl(-) homeostasis and reversed the hyperalgesia. Gene-targeted mice in which Bdnf was deleted from microglia did not develop hyperalgesia to morphine. However, neither morphine antinociception nor tolerance was affected in these mice. Our findings dissociate morphine-induced hyperalgesia from tolerance and suggest the microglia-to-neuron P2X4-BDNF-KCC2 pathway as a therapeutic target for preventing hyperalgesia without affecting morphine analgesia.

}, keywords = {Animals, Antigens, CD11b, Biophysical Processes, Brain-Derived Neurotrophic Factor, Chlorides, Down-Regulation, Gene Expression Regulation, Homeostasis, Hot Temperature, Hyperalgesia, Ion Channel Gating, Male, Membrane Potentials, Mice, Mice, Inbred C57BL, Mice, Transgenic, Microglia, Morphine, Motor Activity, Naloxone, Narcotic Antagonists, Narcotics, Neurons, Pain Threshold, Patch-Clamp Techniques, Protein Synthesis Inhibitors, Rats, Rats, Sprague-Dawley, Receptors, Purinergic P2X4, Ribosome Inactivating Proteins, Type 1, Rotarod Performance Test, Signal Transduction, Spinal Cord, Symporters, Time Factors, Touch, Vocalization, Animal}, issn = {1546-1726}, doi = {10.1038/nn.3295}, author = {Ferrini, Francesco and Trang, Tuan and Mattioli, Theresa-Alexandra M and Laffray, Sophie and Del{\textquoteright}Guidice, Thomas and Lorenzo, Louis-Etienne and Castonguay, Annie and Nicolas Doyon and Zhang, Wenbo and Godin, Antoine G and Mohr, Daniela and Beggs, Simon and Vandal, Karen and Beaulieu, Jean-Martin and Cahill, Catherine M and Salter, Michael W and Yves De Koninck} }